Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition
Open accessAbstract
Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs), and that inhibition of DNA methylation results in aberrant splicing of ASEs. The methyl-CpG-binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased histone acetylation and aberrant ASE-skipping events. We further show that inhibition of histone deacetylase (HDAC) activity leads to exon skipping that shows a highly significant degree of overlap with that caused by MeCP2 knockdown. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs.
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Hypomethylation of repetitive elements in cancer cells can lead to activation and transposition of endogenous retroviral sequences, promoting genetic instability and tumour development.
“Nevertheless, hypomethylation of these elements is observed in cancer cells 26,27 and this can lead to activation and transposition of the endogenous retroviral sequences thereby promoting genetic instability and tumour development 1 (Figure 2).”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [27]
MeCP2 plays a part in regulating exon splicing.
“Similarly, the mCpG-binding protein MeCP2 was found to play a part in regulating exon splicing113.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [113]
High methylation leads MeCP2 to bind alternatively spliced exons, resulting in exon inclusion.
“In this case, a high methylation level led to MeCP2 binding to alternatively spliced exons, which resulted in exon inclusion (FIG. 4).”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [113]
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- Authors
- Maunakea, A. K., Chepelev, I., Cui, K., & Zhao, K.
- Affiliations
- University of Hawaiʻi at Mānoa (US)
- Cincinnati Children's Hospital Medical Center (US)
- National Institutes of Health (US)
- Corresponding author
- Zhao, Keji
- Venue
- Cell Research
- Published
- 2013-08-13
- Volume
- 23
- Issue
- 11
- Pages
- 1256-1269
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC3817542
- OpenAlex
- W2074898309
- Cited by
- 552
- References
- 46
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 26 · 2023: 32 · 2022: 32 · 2021: 55 · 2020: 47 · 2019: 57 · 2018: 42 · 2017: 57 · 2016: 59 · 2015: 53 · 2014: 48 · 2013: 6
- FWCI
- 24.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University (HCT116)
- National Institutes of Health
- University of California, San Francisco
- National Heart, Lung, and Blood Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- alternative splicing, MeCP2, exon skipping, exon recognition, histone acetylation, histone deacetylase, gene body methylation, methyl-CpG binding proteins, RNA splicing regulation
- MeSH terms
- Cell Line, Exons, Humans, Alternative Splicing, DNA Methylation, HCT116 Cells, Methyl-CpG-Binding Protein 2
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